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Charting Relationships in an Unseen World

"Metagenomics crosses an exceptional number of disciplinary boundaries -- which after all are not respected or recognized by nature but are human inventions." --John Wooley

Bacteria and other microorganisms have colonized nearly every environment on Earth, from deep-sea thermal vents to polar ice to the myriad cavities and crevices of the human body. Collectively, they make up more than half the world’s biomass. Their abundance is equally impressive on a personal scale: Bacterial cells living in and on your body outnumber your own cells by a factor of 10.

In every environment they inhabit, microbes perform crucial functions: sequestering carbon, converting nitrogen and other elements into forms that plants and animals can use, metabolizing sugars, amino acids, and vitamins in the human gut, and cleaning up environmental toxins. Microbes' metabolic capabilities can also be tapped for human benefit, in wastewater treatment, soil and crop management, and biofuel and pharmaceutical development, to cite a few important examples. The better we understand how they function, the more we benefit.

(Courtesy of Jo Handelsman and Yale University)

Jo Handelsman

The traditional way to study microorganisms is by isolating and growing individual species in laboratory culture. But the vast majority of microbes -- 99.9%, according to some estimates -- can't be cultured in a laboratory dish and so, until recently, have remained nearly invisible to science. Researchers know little about the diversity of microbial species, what functions they serve, how they interact with one another and with their host environments, and how they respond to environmental changes.

That situation is changing, thanks to the advent of high-throughput sequencing technologies coupled with computational tools for analyzing massive, complex data sets. Together, these advances have made it possible for investigators to study the composition and functions of microbial communities containing thousands of species sampled directly from their natural habitats, without the need to culture the organisms, or even to distinguish one species from another. "We're just at the beginning of what I think will be an explosion of knowledge about the microbial world," says Yale University molecular biologist Jo Handelsman, who in 1998 coined the term "metagenomics" to describe methods for studying microbial communities in aggregate. "We've been using petri plates as the prism through which we look at microbes for 150 years," she says. "Now we're looking at vastly more species. That's part of the thrill of it: that we don't know what we're going to find. It really is brand-new life forms that we're seeing."

Intense interest, rapid development

Scientists studying the microbial communities that live in and on the human body -- the human microbiome -- are examining the role of microbes in many different areas of human health: obesity, digestive diseases, esophageal cancer, psoriasis, and sexually transmitted diseases, among others. Marine scientists are exploring how the environment influences microbes' role in carbon cycling. Soil scientists are probing the soil metagenome's ability to produce antimicrobials, which offers the potential for developing new antibiotics and may underlie the spread of antibiotic resistance.

(University of Maryland)

Jacques Ravel

Meanwhile, the technologies that underpin metagenomics are advancing rapidly. "Back in the dark ages of 2007, when we did our first analysis of several hundred microbial communities, we had half a million sequences and that seemed like a lot," says University of Colorado, Boulder, microbiologist Robin Knight. "Now we're routinely dealing with hundreds of millions of sequences, and soon it will be billions. Every year, just about, it's another order of magnitude increase in sequencing capacity for about the same cost."

The scientific community's excitement about metagenomics is reflected in the myriad agencies and private foundations investing in it. "There's a lot of money being poured into this field," says Jacques Ravel, a microbial genomics scientist at the University of Maryland School of Medicine's Institute for Genome Sciences in Baltimore.

Federal agencies making major investments include the National Science Foundation (NSF), the Department of Energy (DOE), the U.S. Department of Agriculture, and the National Institutes of Health, which in 2008 launched the 5-year, $150 million Human Microbiome Project (HMP) from the NIH Common Fund. That project's goals are to catalog the microbes that inhabit the human body, identify their role in health and disease, and create tools -- such as reference data sets, a data resource center, and improved computational technologies -- that can be used to study the human microbiome. HMP is a one-time pot of money, and most of the grants have already been allocated, but NIH hopes the project will spur applications for institute-specific projects, says Maria Giovanni, assistant director for microbial genomics and advanced technologies in the National Institute for Allergy and Infectious Diseases's Division of Microbiology and Infectious Diseases. "If that didn't happen," she says, "it would be like having a party and nobody comes."

Many disciplines, few boundaries

(Courtesy of John Wooley)

John Wooley

"Metagenomics crosses an exceptional number of disciplinary boundaries -- which after all are not respected or recognized by nature but are human inventions," says University of California, San Diego (UCSD), biochemist and Associate Vice Chancellor of Research John Wooley. Metagenomics training similarly crosses boundaries: Researchers are trained in microbiology, systems biology, ecology, genomics, plant biology, marine biology, soil science, bioinformatics, bioengineering, chemical engineering, biogeochemistry, biochemistry, biophysics, computer science, statistics, and clinical sciences including medical microbiology, gastroenterology, dermatology, and oral science.

The balance of skills needed varies from project to project. Wooley says some current UCSD studies combine bioinformatics, microbiology, ecology, and genomics. Others add structural biology, biophysics, and deep statistical analyses; or marine biology and physical oceanography; or pharmacology and pharmacogenomics. The skills and knowledge needed for doing metagenomics research are so broad, he says, that disciplinary divisions “are not going to be first on any researcher's mind." What will be first, he says, "is getting the right tool set together to answer the question at hand."

Assembling the tool set

No university offers a graduate training program in metagenomics per se; instead, just as molecular biology has been incorporated into many disciplines, metagenomics is also being added to a wide range of fields. Those seeking training in metagenomics should search for an ideal research adviser -- in whatever field they're most interested in -- working in an excellent environment. The best training programs have several faculty members who are involved in metagenomics research, in different disciplines.

Metagenomics research requires deep disciplinary training in microbiology -- with particular focus on molecular biology, systems biology, and genomics -- and expertise in bioinformatics and statistics. Computer skills are likely to be especially marketable as sequencing technologies advance. The third generation of sequencers, expected soon, will increase the rate of data collection, putting computing even further behind than it already is, predicts microbiologist Julian Marchesi of Cardiff University in the United Kingdom. "It is definitely a barrier, and if I were looking to employ someone, it would be an advantage if they were able to write code for a computer to aid in processing the DNA data being processed."

Although keeping abreast of rapidly evolving sequencing technology is critical to doing metagenomic research, it's even more important to be able to ask rigorous questions; in other words, you need a strong disciplinary grounding. Ravel says, "I tell my grad students that you have to be a good bench scientist first, and if you can combine the bioinformatics and the biology, your chance of getting a job is already twice as much."

The job market

(Department of Energy)

Charlene Weatherwax

Compared with other academic life-science fields, the metagenomics job market already looks strong, but it's impossible to quantify -- and too soon to know what the future holds, says Matthew Kane, director of ecosystem science in the National Science Foundation's (NSF's) Division of Environmental Biology. "Metagenomics is a term that was known only to microbial ecologists until about 5 years ago, so I think we're still on the cusp of the big impact." He compares the field's current state to the early days of bioinformatics: In the 1980s, he says, bioinformatics skills were seen to be useful but "you couldn't point to all kinds of people getting jobs in bioinformatics. Today, people who are at the intersection of computer science and biology are very competitive in the job market."

The strongest candidates for those jobs, Wooley says, will know something about several aspects of their field, they'll know statistics and microbiology, and they'll be prepared to make a strong contribution in a specific area of inquiry, such as population evolution, protein diversity, species diversity, or understanding pathways and networks in microbes.

A sense of adventure

In addition, succeeding in metagenomic research requires a certain mindset. "You have to be able to stand back and observe the pattern and how all the pieces fit together," says Sharlene Weatherwax, director of the Department of Energy Office of Science's Biological Systems Science Division. That way of looking at science isn't for everyone, Weatherwax says. "Not everyone wants to do a jigsaw puzzle."

It also helps to be comfortable with not knowing, Knight says, because right now so little is known. "You have to see that as an exciting challenge rather than a discouraging limitation."

- The Department of Energy (DOE) Genomic Science Program supports metagenomic research through three Bioenergy Research Centers (whose overall focus is to spur basic research in the development of biofuels), as well as through individual research grants. (In addition to its grant programs, DOE's Joint Genome Institute, based in Walnut Creek, California, conducts metagenomic sequencing and analysis, as well as other microbiological work that is foundational to being able to perform metagenomic analyses.)